肝细胞SIRT7缺失介导PAI-1分泌激活星状细胞促进肝纤维化

SIRT7 deficiency in hepatic cell mediates PAI-1 secretion,activating hepatic stellate cell and promoting liver fibrosis

目的:受肝纤维化影响的人群广泛,而治疗方法缺乏。沉默信息调节因子2相关酶类7(silencing information regulator 2 related enzyme,SIRT7)是组蛋白去乙酰化酶sirtuin家族的成员,参与细胞衰老、代谢和炎症反应等多种生理学过程。据报道,SIRT7在许多肝脏疾病如肝癌和脂肪性肝炎中发挥重要作用,本研究旨在探究SIRT7在肝纤维化中的功能。方法:通过四氯化碳(CCl_(4))隔天腹腔注射,在野生型小鼠和肝细胞SIRT7特异性敲除小鼠中建立肝纤维化模型并进行损伤与纤维化表型测定。采用原代细胞分离与纯化技术进行体外共培养实验,结合阵列图进一步分析确定SIRT7缺失影响肝星状细胞(hepatic stellate cells,HSC)激活的分子媒介。结果:SIRT7缺失加剧了CCl_(4)诱导的肝损伤和纤维化表型。进一步研究表明,SIRT7缺失介导肝细胞PAI-1分泌差异激活HSC从而促进肝纤维化。结论:SIRT7介导的信号在肝损伤和纤维化中发挥重要作用,靶向SIRT7可能是治疗肝纤维化的有效途径。

Background The population affected by liver fibrosis is extensive,yet treatment options are lacking.SIRT7,a member of the sirtuin family of histone deacetylases,is involved in various physiological processes such as cellular aging,metabolism,and inflammatory responses.It has been reported that SIRT7 plays crucial roles in many liver diseases,including hepatocellular carcinoma and non-alcoholic fatty liver disease,but its function in liver fibrosis remains unclear.Methods A liver fibrosis model was established by alternate-day intraperitoneal injection of CCl_(4)in both wild-type mice and hepatocyte SIRT7 knockout mice,followed by assessment of injury and fibrosis phenotypes.Subsequently,primary cells were used for in vitro co-culture experiments,combined with array analysis to further determine the mediators of hepatic stellate cell(HSC)activation affected by SIRT7 deficiency.Conclusion SIRT7 deficiency exacerbated CCl_(4)-induced liver injury and fibrosis phenotypes.Further research indicated that SIRT7 deficiency mediated differential activation of hepatic stellate cells(HSCs)through hepatocyte PAI-1 secretion,thereby promoting liver fibrosis.Our results suggested that SIRT7-mediated signaling plays a significant role in liver injury and fibrosis,and therapeutic targeting SIRT7 may be an effective approach for treating liver fibrosis.